Background/Purpose:

Proteins in the BCL-2 family are key regulators of apoptosis, or programmed cell death.  We report here that continuous daily treatment with 30mpk venetoclax (ABT-199), a selective BCL-2 inhibitor, produces a sustained lymphocyte depletion in peripheral blood that correlates with reduced disease severity in NZBWF1 lupus mice. The time course for lymphocyte depletion, recovery and efficacy following multiple dosing regimen was investigated.

Methods:

For lymphocyte recovery studies, C57BL6 mice were treated with a single 30 mpk dose of venetoclax or once daily 30 mpk dose for 7 days. Changes in lymphocytes in peripheral blood were assessed weekly by a Celldyn 3700 blood analyzer. For efficacy studies, venetoclax was administered once daily to NZBWF1 lupus mice by one of three dosing schedules: (1) continuous dosing for 28 weeks (30 mpk); (2) dosing on day 1 of a 7 day cycle for 28 cycles (100mpk); or (3) intermittent dosing on days 1-7 of a 28-day cycle for 7 cycles (30 or 100 mpk). Proteinuria and survival data are presented as Kaplan-Meyer survival curves. B and T cells in peripheral blood were analyzed by flow cytometry. 

Results:

While a single 30 mpk dose of venetoclax leads to significant lymphocyte depletion within 24 hours followed by recovery to baseline by day 7, 7 days of continuous dosing is followed by lymphocyte recovery by day 28. Weekly proteinuria and survival endpoints reveal comparable efficacy between the intermittent dosing cycles at 100 mpk  dose of venetoclax and continuous dosing at 30 mpk of venetoclax. Numbers of B and T cells from the first two intermittent cycles showed trends toward partial or complete recovery by day 28 versus sustained depletions in animals with continuous dosing.

Conclusion:

We have identified an intermittent dosing schedule for venetoclax that conveys compelling efficacy in NZBWF1 lupus mice without persistent lymphocyte depletion. This dosing regimen may translate into a more favorable benefit-risk profile and hence has been incorporated into a phase 1 trial in SLE patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lymphocyte-depletion-recovery-and-efficacy-in-nzbwf1-lupus-mice-following-continuous-or-intermittent-dosing-regimen-of-venetoclax-abt-199-a-potent-and-selective-bcl-2-inhibitor/